The proposed investigation is intended to elucidate the ecological conditions and population and genetic processes responsible for: (1) the evolution of multiple antibiotic resistance plasmids and their spread between lineages (clones) and species of bacteria, (2) the evolution of multiple antibiotic resistance determined by chromosomal gene mutations; and iii) the maintenance and effects of phage in bacterial populations and the evolution of lysogeny. We will develop and analyze the properties of mathematical models for: (1) The evolution of single plasmids carry~g multiple antibiotic resistance genes from separate conjugative plasmids, conjugative and nonconjugative plasmids, and from combinations of conjugative plasmid and chromosome-borne resistance genes (transposons). (2) The population genetics of chromosomal gene antibiotic resistance in free-living populations of bacteria, populations of bacteria infecting individual antibiotic-treated vertebrate hosts,and in communities of hosts (the epidemiology of antibiotic resistance). (3) The population dynamics of lytic and temperate phage in closed habitats and in communities with multiple habitats. Using experimental populations of E. coli and its plasmids, lytic and temperate phages, we will estimate the parameters of these models and evaluate the predictions made from the analysis of their properties. For both antibiotic resistance studies, population experiments will be performed in vivo, antibiotic-treated mice, as well as in vivo, serial transfer and chemostat culture. These mouse studies are intended to; i) ascertain the contribution of antibiotic treatment to the movement of antibiotic resistance (and other) plasmids between separate lineages of bacteria, il) evaluate the effects of different regimes of antibiotic treatment on the origin and rate of ascent of bacteria carrying mutations for resistance to one or more antibiotics.